FDA Grants Priority Review to Liso-Cel Applications in MCL and FL

Lymphomas: © immimagery - stock.adobe.com

• The promising chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel (liso-cel; Breyanzi) gained priority review for relapsed/refractory (R/R) follicular lymphoma (FL) and mantle cell lymphoma (MCL) in both the United States and Japan. The FDA target action dates are May 23 and May 31, 2024, respectively.
• Clinical trials showed high response rates and durable responses. Notably, TRANSCEND FL (NCT04245839) demonstrated 89.8% duration of response (DOR) and 91.3% progression-free survival (PFS) at 12 months.
• Neutropenia was the most common adverse event (AE), while serious cytokine release syndrome (CRS) and neurological events were infrequent. The safety profile appears manageable.

The FDA has granted priority review to the supplemental biologics license applications (sBLAs) of liso-cel, a CAR T-cell therapy, for the treatment of R/R FL and MCL after a Bruton tyrosine kinase inhibitor (BTKi).¹

Japan’s Ministry of Health, Labor, and Welfare has also accepted the supplemental new drug application of liso-cel for R/R FL.

The sBLAs are supported by findings from the TRANSCEND FL and TRANSCEND NHL 001 (NCT02631044) clinical trials which showed promising complete response rates (CRRs) and durable responses. The FDA has issued Prescription Drug User Fee Act target action dates of May 23, 2024, for liso-cel in R/R FL and May 31, 2024, in R/R MCL.

“Patients living with follicular lymphoma and mantle cell lymphoma often experience cycles of remission and relapse with multiple lines of treatment, and we are committed to delivering innovative treatment solutions to this population,” said Anne Kerber, MD, senior vice president, Head of Late Clinical Development, Hematology, Oncology, Cell Therapy, Bristol Myers Squibb, in a press release. “[Liso-cel] offers the potential for durable response, and these filing acceptances in the U.S. and Japan support our commitment to delivering our best-in-class CAR T-cell therapy treatments to as many eligible patients as possible.”

TRANSCEND FL

Updated findings from TRANSCEND FL were presented at the 2023 American Society of Hematology Annual Meeting.² At 12 months, liso-cel demonstrated a DOR of 89.8% and PFS was 91.3%. At median follow-ups of 16.8 and 17.8 months, the median DOR and PFS were not reached, respectively.

Regarding safety, neutropenia was the most common grade 3 or higher treatment-emergent AE occurring in 52% of patients. Twelve patients (52%) experienced CRS; however, all these events were grade 1 or 2. Neurological events were reported in 17% (n = 4) patients, and 4% (n = 1) were grade 3. No grade 4 or 5 neurological events were reported.

The primary end point of TRANSCEND FL was overall response rate (ORR).³ Secondary end points included CRR, DOR, PFS, overall survival (OS), AEs, and pharmacokinetics.

Patients were pretreated with intravenous (IV) fludarabine at 30 mg/m2/day and IV cyclophosphamide at 300 mg/m2/day for 3 days. Liso-cel was then administered at a target dose of 100 x 106 CAR-positive viable T cells.

To be eligible for the trial, patients with R/R FL needed to have received at least 1 prior line of anti-CD20 and alkylating agent therapy, as well as 1 prior line of systemic therapy. Patients also needed an ECOG performance status of 0 or 1, adequate organ function, and adequate vascular access for the leukapheresis procedure. Patients with central nervous system (CNS) involvement, history of another primary malignancy, history of active human immunodeficiency virus, or history of uncontrolled infection were not eligible for participation.

TRANSCEND-NHL-001

Updated findings from the phase 1 TRANSCEND-NHL-001 trial were published in December 2023.⁴ Investigators reported that, at a median follow-up of 16.1 months (range, 0.4-60.5), the ORR was 83.1% (95% CI, 73.3%-90.5%) and the CRR was 72.3% (95% CI, 61.4%-81.6%). The median DOR was 15.7 months (95% CI, 6.2-24.0). The median PFS was 15.3 months (95% CI, 6.6-24.9).

The most common grade 3 or greater treatment-emergent AE was neutropenia (56%). CRS was observed in 61% of patients, with only 1% being grade 3 or 4. Neurological events were reported in 31% of patients, with 9% reported as grade 3 or 4.

The primary end points of TRANSCEND-NHL-001 were treatment-related AEs, dose-limiting toxicities, and ORR.⁵ The secondary end points were CRR, DOR, PFS, OS, health-related quality of life, and pharmacokinetics.

Following lymphodepletion, patients received either 1 or 2 IV doses of liso-cel. Patients were required to have an ECOG performance status of 0 or 1, adequate laboratory levels, adequate cardiac function, and adequate vascular access. Patients were not eligible to participate in the trial if they had active CNS involvement, cardiovascular disease, active hepatitis infection, or another active infection.

REFERENCES:

1. Regulatory applications accepted in the U.S. and Japan for Bristol Myers Squibb’s Breyanzi (lisocabtagene maraleucel) in relapsed or refractory follicular lymphoma (FL) and relapsed or refractory mantle cell lymphoma (MCL). News release. Bristol Myers Squibb. January 30, 2024. Accessed January 30, 2024. http://tinyurl.com/32ze8reu

2. Morschhauser F, Dahiya S, Palomba ML, et al. TRANSCEND FL: Phase 2 study primary analysis of lisocabtagene maraleucel as second-line therapy in patients with high-risk relapsed or refractory follicular lymphoma. Presented at: 2023 American Socitery of Hematology Annual Meeting & Exposition, December 9-12; San Diego, California. Abstract 602.

3. A study to evaluate the efficacy and safety of JCAR017 in adult subjects with relapsed or refractory indolent B-cell non-Hodgkin lymphoma (NHL) (TRANSCEND FL). ClinicalTrials.gov. Updated November 30, 2023. Accessed January 30, 2024. https://clinicaltrials.gov/study/NCT04245839

4. Wang M, Siddiqi T, Gordon L, et al. Lisocabtagene maraleucel in relapsed/refractory mantle cell lymphoma: primary analysis of the mantle cell lymphoma cohort from TRANSCEND NHL 001, a phase I multicenter seamless design study. J Clin Oncol. Published online December 10, 2023. doi:10.1200/JCO.23.02214.

5. Study evaluating the safety and pharmacokinetics of JCAR017 in B-cell non-Hodgkin lymphoma (TRANSCEND-NHL-001). ClinicalTrials.gov. Updated March 3, 2023. Accessed January 30, 2024. https://clinicaltrials.gov/study/NCT02631044